title: The guinea pig atrial A1 adenosine receptor reserve for the direct negative inotropic effect of adenosine.
abstract: Although the A1 adenosine receptor (A1 receptor), the main adenosine receptor type in cardiac muscle, is involved in powerful cardioprotective processes such as ischemic preconditioning, the atrial A1 receptor reserve has not yet been quantified for the direct negative inotropic effect of adenosine. In the present study, adenosine concentration-effect (E/c) curves were constructed before and after pretreatment with FSCPX (8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 receptor antagonist, in isolated guinea pig atria. To prevent the intracellular elimination of the administered adenosine, NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, was used. As expected, NBTI alone and FSCPX-pretreatment alone shifted the adenosine E/c curve to the left and right, respectively. However, in the presence of NBTI, FSCPX-pretreatment appeared to increase the maximal response to adenosine. By means of the receptorial responsiveness method (RRM), our recently developed procedure, adenosine E/c curves generated in the presence of NBTI were corrected for the bias caused by the endogenous adenosine accumulated by NBTI. The corrected curves indicate a substantial A1 receptor reserve for the direct negative inotropy evoked by adenosine. In addition, our results suggest that accumulation of an endogenous agonist may bias the E/c curve constructed with the same or similar agonist that can lead to seemingly paradoxical results.
authors.affiliation: Department of Pharmacology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Kiss
authors.forename: Krisztian
authors.initials: K
authors.lastname: Pak
authors.forename: Judit
authors.initials: J
authors.lastname: Zsuga
authors.forename: Bela
authors.initials: B
authors.lastname: Juhasz
authors.forename: Balazs
authors.initials: B
authors.lastname: Varga
authors.forename: Andras J
authors.initials: AJ
authors.lastname: Szentmiklosi
authors.forename: David D
authors.initials: DD
authors.lastname: Haines
authors.forename: Arpad
authors.initials: A
authors.lastname: Tosaki
authors.forename: Rudolf
authors.initials: R
authors.lastname: Gesztelyi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D014970:Xanthines; C100640:8-cyclopentyl-3-(3-((4-(fluorosulfonyl)benzoyl)oxy)propyl)-1-propylxanthine; C048599:N(6)-cyclopentyladenosine; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine; D000241:Adenosine